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Publication numberUS5716842 A
Publication typeGrant
Application numberUS 08/649,632
PCT numberPCT/EP1995/003580
Publication dateFeb 10, 1998
Filing dateSep 12, 1995
Priority dateSep 30, 1994
Fee statusPaid
Also published asDE4435107C1, EP0731732A1, EP0731732B1, EP1022059A2, EP1022059A3, EP1022059B1, WO1996010456A1
Publication number08649632, 649632, PCT/1995/3580, PCT/EP/1995/003580, PCT/EP/1995/03580, PCT/EP/95/003580, PCT/EP/95/03580, PCT/EP1995/003580, PCT/EP1995/03580, PCT/EP1995003580, PCT/EP199503580, PCT/EP95/003580, PCT/EP95/03580, PCT/EP95003580, PCT/EP9503580, US 5716842 A, US 5716842A, US-A-5716842, US5716842 A, US5716842A
InventorsVolker Baier, Ulrich Bodner, Ulrich Dillner, Johann Michael Kohler, Siegfried Poser, Dieter Schimkat
Original AssigneeBiometra Biomedizinische Analytik Gmbh
Export CitationBiBTeX, EndNote, RefMan
External Links: USPTO, USPTO Assignment, Espacenet
Miniaturized flow thermocycler
US 5716842 A
Abstract
A miniaturized thermocycler is provided for carrying out thermally controlled biochemical or biological melecular processes, in particular polymerase chain reactions. The aim of the invention is to provide a miniaturized thermocycler which enables such reactions to be carried out more effectively, avoids the problem of parasitic heat absorbers and can be manufactured inexpensively in series. This aim is achieved by virtue of the fact that the sample holder (1) is designed as a series of meanders winding in a plane, the sample holder (1) has a groove in a wall and closed over by a cover, the groove passing alternately through comparable heating zones (2) and cooling zones (3), located at intervals along the groove, as it meanders.
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Claims(11)
I claim:
1. A miniaturized flow thermocycler comprising:
a substrate plate having grooves formed in a plane;
a cover plate having a first surface for covering said substrate plate and sealing said grooves;
means for interconnecting said grooves to form a meandering sample holding channel for receiving and passing liquid media in one direction; and
means for applying heating and means for applying cooling to alternating portions of said meandering sample holding channel such that said meandering sample holding channel is alternatingly affected creating a plurality of alternating heating zones and cooling zones for said liquid media which are spaced apart from one another to effect alternating heating and cooling of said liquid media as said liquid media passes continuously through said meandering sample holding channel in said one direction whereby said meandering sample holding channel functions as a continuous reaction chamber having alternating heating and cooling areas.
2. A miniaturized flow thermocycler according to claim 1, wherein:
said substrate plate having said grooves is formed of one of a silicon and a glass, and said grooves are etched in parallel to one another; and
said interconnecting means includes bridging channels formed in said cover to interconnect ends of said grooves to form said meandering sample holding channel.
3. A miniaturized flow thermocycler according to claim 2, wherein:
said cover is formed of a silicon sheet;
said cover has at least one thermally insulating notch formed in a second surface opposite said first surface to form a diaphragm in said cover for sealing portions of said grooves below said diaphragm; and
said at least one thermally insulating notch being interposed between said means for applying cooling and said means for applying heating thereby serving to thermally isolate said means for applying cooling and said means for applying heating.
4. A miniaturized flow thermocycler according to claim 1, wherein at least one of said heating zones and said cooling zones comprise equally long sample flow sections.
5. A miniaturized flow thermocycler according to claim 1, wherein at least one of the heating zones is divided into spaced apart ranges being subject to different temperatures.
6. A miniaturized flow thermocycler according to claim 1, wherein:
said cover is formed of a silicon sheet;
said cover has at least one thermally insulating notch formed in a second surface opposite said first surface to form a diaphragm in said cover for sealing portions of said grooves below said diaphragm; and
said at least one thermally insulating notch being interposed between said means for applying cooling and said means for applying heating thereby serving to thermally isolate said means for applying cooling and said means for applying heating.
7. A miniaturized flow thermocycler apparatus, comprising:
a substrate assembly having a meandering reaction channel in a plane for receiving a liquid media to be passed therethrough in one direction;
said substrate assembly having at least one thermally insulating notch formed in a first surface thereof and substantially parallel to said plane of said meandering reaction channel to form diaphragm portions between a bottom surface of said notch and said meandering reaction channel; and
said thermally insulating notch dividing said first surface of said substrate assembly into at least one heating area and one cooling area for applying and removing heat from said meandering reaction channel, respectively, such that said meandering channel has alternating heating and cooling portions separated from one another by portions of said meandering reaction channel defined by said diaphragm portions to permit alternating heating and cooling of said liquid media as said liquid media passes through said meandering reaction channel in said one direction.
8. The miniaturized flow thermocycler apparatus according to claim 7 wherein said substrate assembly comprises:
a base member having parallel grooves formed therein;
a cover member covering said base member;
said cover member having interconnect grooves formed in a first surface of said cover member, said first surface contacting and sealing said parallel grooves, and said interconnect grooves interconnecting said parallel grooves at ends thereof to form said meandering reaction channel; and
said cover member having said thermally insulating notch formed in a second surface opposite said first surface, said second surface corresponding to said first surface of said substrate assembly, and said thermally insulating notch being formed perpendicular relative to said parallel grooves.
9. The miniaturized flow thermocycler apparatus according to claim 7 wherein said at least one heating area of said first surface has a heating element formed thereon.
10. The miniaturized flow thermocycler apparatus according to claim 7 wherein at least one of said at least one heating area of said first surface is subdivided by a second thermally insulating notch into two first and second heating areas for heating said liquid media to first and second temperatures respectively.
11. A miniaturized flow thermocycler apparatus, comprising:
a substrate assembly having meandering reaction channel in a plane for receiving a liquid media to be passed therethrough in one direction;
said substrate assembly including a cover member having a first surface covering and sealing said meandering reaction channel;
said cover member having thick areas and thin areas defined by at least one recess formed in a second surface of said cover member opposite said first surface, said thin areas thermally insulating said thick areas from one another;
said thick areas and said thin areas being alternatingly disposed along a path of and adjacent said meandering reaction channel; and
alternating ones of said thick areas along said path of said meandering reaction channel being heating areas and cooling areas, respectively, for applying and removing heat from said meandering reaction channel, respectively, such that said meandering reaction channel has alternating heating and cooling portions separated from one another by portions of said meandering reaction channel adjacent said thin areas to permit alternating heating and cooling of said liquid media as said liquid media passes through said meandering reaction channel in said one direction.
Description
BACKGROUND OF THE INVENTION

The invention relates to a miniaturized flow thermocycler applicable in thermally controlled biochemical and biological molecular processes, respectively, particularly for use in so-called polymerase chain reaction methods in which definite sequences out of a mixture of DNA sequences are amplified.

When carrying out thermally controlled biochemical and biological molecular processes, respectively, very often procedure steps at different temperatures are required. Such an exposure to varying temperatures is of particular importance in the so-called polymerase chain reaction.

The polymerase chain reaction method has been recently developed to amplify definite DNA sequences and its essential features have been outlined in "Molekulare Zellbiologie", Walter de Gruyter, Berlin-New York 1994, pg. 256/257' by Damell, J.; Lodish, H.; Baltimore, D. Inter alia, it is essential in the method that mixtures of DNA sequences are subject to definitely varying temperatures. To this end stationary sample treatment devices are employed where the respective samples are inserted into reaction chambers for being subject to a periodical hot-cold-temperature cycle, the respectively desired DNA sequences being amplified depending on the specifically preselected primers. The efficiency of the reaction chambers known heretofore is considered insufficient. Therefore a miniaturized reaction chamber has recently been proposed (Northrup et al, DNA Amplification with Microfabricated reaction chamber, 7th International Conference on Solid State Sensors and Actuators, Proc. Transducers 1993, pg. 924-26), which permits a four-times faster amplification of desired DNA sequences compared to known arrangements. The reaction chamber which is capable to of receiving up to 50 μreaction fluid comprises a structurized silicon cell of a longitudinal extension on an order of size of 10 mm which is, in one sample injection direction, sealed by a thin diaphragm via which the temperature exposure is executed by miniaturized heating elements. Also with this device the DNA sequence to be amplified is inserted via micro-channels into the cell, subjected to a polymerase chain reaction and subsequently drawn off. Irrespective of the advantages obtained with the device, it still exhibits the disadvantage that the reaction chamber has to be heated and cooled in its entity which only permits limited rates of temperature changes. Particularly at a further reduction of the sample sizes, the parasitic heat capacity of the reaction chamber and, if employed, of a tempering block becomes more dominant to the reaction liquid so that the high temperature changing rates, otherwise feasible with small liquid volumes, cannot be achieved, which renders the efficiency of the method comparatively low. Additionally, a comparatively expensive control system is required to obtain a respectively stable temperature control of the reaction liquid furthermore, the heating and cooling power applied, respectively, is substantially consumed in the ambient units rather than in the reaction liquid.

Furthermore, a thermocycler operating on the flow principle is known from the U.S. Pat. No. 5,270,183 in which the reaction liquid to be amplified passes through a tube being subsequently wound once or multifold around a plurality of cylinders which are kept on different temperatures. As it is, such an arrangements permits amplification of even comparatively low sample amounts down to 25 μl. However, such a device is very difficult to handle and requires considerable skill on the side of the apparatus producer so that it is entirely unsuited for large scale production.

SUMMARY OF THE INVENTION

It is an object of the present invention provide a miniaturized thermocycler which, compared to the state of art, permits to more effective control of biochemical and biological molecular, respectively, processes and, in particular, the method for polymerase chain reaction, which obviates the problem of parasitic heat capacities and which is inexpensive in manufacture.

The invention is based on the idea to utilize structurizing technologies known from so-called microsystem techniques in order to provide reaction chambers which permit dynamic reaction treatment of even very low amounts of, partially, very expensive materials.

An embodiment of receptacle portions for receiving a sample material ensures that the sample portion volumes under treatment in respective heating and cooling zones are subjected to a homogeneous temperature which also increases the output of the substance to be amplified. Furthermore, due to the omission of heating and cooling processes of wall materials by virtue of the arrangement, and due to a severe minimizing of the parasitic heat absorption and heat affects, the expenditures for control systems are considerably reduced, apart from a remarkable reduction of time for the entire cycling process. Only as much heating and cooling power has to be fed in as carried in the reaction liquid stream. Additionally, the embodiment of the thermocycler not only permits a continuous process but also a serial operation in which different substances are subsequently injected into the thermocycler without the danger of mixing with sample materials still in the arrangement which is simply obtained by inserting a small buffer gas volume. The abovementioned advantages also ensure an automation of the method for polymerase chain reaction.

Furthermore, an easy combination with other methods is feasible such as the micro-gel-electrophoresis, the micro-capillary-chromatography and other micro separating and analyzing methods.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows a plan view of an inventional reaction chamber in which the path of the sample liquid is embodied by microstructured flow paths, and

FIG. 2 shows a lateral section of a reaction chamber according to FIG. 1.

DETAILED DESCRIPTION OF THE INVENTION

In FIG. 1 a reaction chamber, in which a sample liquid path, is embodied by a micro-structured low path is schematically represented. FIG. 2 shows a not-to-scale lateral section of the embodiment. In the embodiment grooves 8, which are in parallel to one another in the present example, are wet-chemically etched into a plate 10 having a size of about 10*15 mm and a thickness of 500 μm and being made of glass or silicon. Alternatively slots can be provided instead of the grooves 8, in this case the resulting frame, on the one side, is closed over its entire area by a solid plate. Further to the present example, the open groove ranges are closed by a cover 9 comprising components above the axis X--X, as shown in FIG. 2. According to the invention, the cover 9 is a silicon sheet in which two heat insulating notches 12 are provided. The notches form at their base portion a diaphragm-like seal 13 of about 1 μm thickness which covers the groove ranges constituting reaction liquid duration zones between heating and the cooling zones. In FIG. 2 the central silicon projection is provided with a thin-layer heating element 15 on its top which effects the heating of the sample material on its remote base. A thermo-regulated cooling system (not shown in detail) is provided on the two remaining lateral silicon projections of this embodiment. Bridging channels 11, provided in the cover 9, connect respective adjacent individual groove end portions to provide a continuous reaction liquid flow in the present example. It is feasible to provide the required inlets and outlets either in the plate 10 (as indicated in FIG. 1) or in the cover 9. In the example, the disclosed entire device is attached to a mount 16 made of a glass of low thermal conductivity. In the present example the individual grooves 8 have a width of 500 μm and a length of somewhat under 100 mm at a groove depth of 400 μm which yields an entire groove length of 0.4 m including the paths for the bridges. Suitably, it is feasible to inject sample volumes of about 10 to 200 μl into the flow thermocycler which corresponds to conventional sample amounts. Since the given groove dimensions do not by far exhaust the possibilities of, dimensions can already be produced today which permit the injection of sample volumes in an order of size of 0.1 μl for specific applications.

With the embodiment of FIGS. 1 and 2 an entire amplification cycle time of 40 min at a maximum output is attainable with feasible flow rates of about 0.1 μl/sec., duration of the samples in the heating zones for about 20 sec., in the cooling zones for 30 sec., and in the intermediate zones for 10 sec., using forty individual grooves, the cycle time represents a considerable reduction of the shortest time known heretofore apart from a simultaneously increased output.

It lies within the scope of the example of the present invention to embody the heating zone divided into two partial ranges in such a manner that, considered in the direction of flow, a first heating zone of, for example, 4 mm width results, followed by a not shown thermally insulating zone of 1 mm, the latter, in turn, is followed by a second heating zone of 2 mm width. Thus it is feasible to set, via a respective heating power control, the first heating zone to a temperature of 72° C. and the second heating zone to a temperature of 92° C. The second heating zone can be followed by a second thermally insulating zone of, for example, 3 mm width, followed by a cooling zone of, for example, 3 mm width kept by a secondary cooling controller at 55° C. A miniaturized thermocycler embodied in such a manner is particularly suited for performing polymerase chain reactions. To this end, via an inlet, a mixture of template, nucleosidtriphosphate, primers, and taq-polymerase in a buffer solution is injected, the respective composition of which is determined according to the state of art. The flow rate is set to about 8 μl/min. so that the duration per period is about 1 minute, 20 sec. falling to the first heating zone, 10 sec. to the second heating zone, 15 sec. to the cooling zone and 5 sec. to each thermal insulating zone. Hence, 40 minutes are required for passing the entire miniaturized thermocycler. During this time, forty amplification cycles take place in a volume unit of 2 μl. When prolonged to 44 minutes (10% prolongation of time) 34 μl are amplified.

The reaction chamber can be easily series produced and is inexpensive, it can be produced over a wide variety of geometries so that an adaptation to varying applications does not involve any difficulties.

Patent Citations
Cited PatentFiling datePublication dateApplicantTitle
US5270183 *Feb 8, 1991Dec 14, 1993Beckman Research Institute Of The City Of HopePolymerase chain reaction to amplify DNA
US5498392 *Sep 19, 1994Mar 12, 1996Trustees Of The University Of PennsylvaniaMesoscale polynucleotide amplification device and method
US5587128 *Nov 14, 1994Dec 24, 1996The Trustees Of The University Of PennsylvaniaPolymerase chain reaction
FR2650657A1 * Title not available
WO1991016966A1 *May 8, 1991Nov 14, 1991Pharmacia Biosensor AbMicrofluidic structure and process for its manufacture
WO1992013967A1 *Jan 21, 1992Aug 20, 1992Beckman Res Inst City HopeDevice and method for the automated cycling of solutions between two or more temperatures
WO1993022058A1 *Apr 29, 1993Nov 11, 1993Univ PennsylvaniaPolynucleotide amplification analysis using a microfabricated device
WO1994005414A1 *Aug 31, 1993Mar 17, 1994Univ CaliforniaMicrofabricated reactor
Non-Patent Citations
Reference
1"DNA Amplification With A Microfabricated Reaction Chamber", (by M. Allen Northrup, Michael T. Ching, Richard M. White, and Robert T. Watson, 7th International Conference on Solid State Sensors and Actuators, Proc. Transducers 1993, pp. 924-926).
2"Molekulare Zellbiologie", (by Darnell, J.; Lodish, H.; Baltimore, D., published by Walter de Gruyter, Berlin-New York 1994, pp. 256-257).
3 *DNA Amplification With A Microfabricated Reaction Chamber , (by M. Allen Northrup, Michael T. Ching, Richard M. White, and Robert T. Watson, 7th International Conference on Solid State Sensors and Actuators, Proc. Transducers 1993, pp. 924 926).
4 *Molekulare Zellbiologie , (by Darnell, J.; Lodish, H.; Baltimore, D., published by Walter de Gruyter, Berlin New York 1994, pp. 256 257).
Referenced by
Citing PatentFiling datePublication dateApplicantTitle
US6200531May 11, 1998Mar 13, 2001Igen International, Inc.Apparatus for carrying out electrochemiluminescence test measurements
US6372486Nov 29, 1999Apr 16, 2002Hybaid LimitedThermo cycler
US6432695Feb 16, 2001Aug 13, 2002Institute Of MicroelectronicsMiniaturized thermal cycler
US6509186May 1, 2001Jan 21, 2003Institute Of MicroelectronicsMiniaturized thermal cycler
US6521447Jul 3, 2002Feb 18, 2003Institute Of MicroelectronicsFor simultaneous treatment of multiple individual samples (DNA) in independent thermal protocols; for use in polymerase chain reactions
US6556940Apr 5, 2000Apr 29, 2003Analytik Jena AgFor performing polymerase chain reactions; temperature of multiwell sample plates is modulated via thermoelectric pump
US6640891Sep 5, 2000Nov 4, 2003Kevin R. OldenburgRapid thermal cycling device
US6770471Sep 26, 2001Aug 3, 2004Stmicroelectronics S.R.L.Integrated chemical microreactor, thermally insulated from detection electrodes, and manufacturing and operating methods therefor
US6929731Mar 7, 2001Aug 16, 2005Northeastern UniversityParallel array of independent thermostats for column separations
US6929968Jun 23, 2004Aug 16, 2005Stmicroelectronics S.R.L.Integrated chemical microreactor, thermally insulated from detection electrodes, and manufacturing and operating methods therefor
US6974693Jun 23, 2004Dec 13, 2005Stmicroelectronics S.R.L.semiconductors; integratd circuits; for detecting DNA amplification
US7015030Jul 28, 2000Mar 21, 2006Genset S.A.Microfluidic devices and uses thereof in biochemical processes
US7025120Jan 31, 2003Apr 11, 2006Oldenburg Kevin RCovering for well plastes; covering held with pins; heasting; controlling temperature
US7172736Jul 28, 2003Feb 6, 2007Casio Computer Co., Ltd.Compact chemical reactor and compact chemical reactor system
US7175817Aug 4, 2003Feb 13, 2007Casio Computer Co., Ltd.Compact chemical reactor and chemical reaction system
US7311794May 24, 2005Dec 25, 2007Wafergen, Inc.Methods of sealing micro wells
US7373968Jul 16, 2004May 20, 2008Kevin R. OldenburgMethod and apparatus for manipulating an organic liquid sample
US7431898Mar 28, 2003Oct 7, 2008Casio Computer Co., Ltd.Thin-film heater formed on body to oppose reaction flow path; fuel cells
US7531016Mar 19, 2003May 12, 2009Casio Computer Co., Ltd.Chemical reactor with plurality of bonded substrates; heater for flow path; heat radiation prevention film covers exterior surface
US7553448Jun 19, 2003Jun 30, 2009Bioveris Corporationelectrode comprises a platinum, iridium alloy with predetermined weight percent of each component; organometallic complex comprises a ruthenium or osmium-tris-bipyridine moiety in the presence of tripropylamine; increase operational lifetime and performance; reusable; biological assay and medical test
US7611674Jan 11, 2007Nov 3, 2009Applied Biosystems, LlcHeating/ cooling device for control of a reaction vessel receiver having several recesses arranged in a regular pattern to receive a microtiter plate with severalreaction vessels; thermocycler receiver divided into thermally decoupled segments actuated independentally; automatic; robotics; DNA
US7614444May 7, 2004Nov 10, 2009Oldenburg Kevin RRapid thermal cycling device
US7618811Feb 24, 2005Nov 17, 2009Thermal GradientMultilayer apparatus for propagation of biopolymer sequences
US7622296May 24, 2005Nov 24, 2009Wafergen, Inc.Sealed microarrays with transparent cover are placed within indium tin oxide heater; condensation prevention; PCR; high-throughput and low-cost amplification of nucleic acids
US7727479Jun 12, 2006Jun 1, 2010Applied Biosystems, LlcDevice for the carrying out of chemical or biological reactions
US7833709May 24, 2005Nov 16, 2010Wafergen, Inc.Thermo-controllable chips for multiplex analyses
US7972778Mar 11, 2004Jul 5, 2011Applied Biosystems, LlcUsing multicompartment apparatus for replicating nucleotide sequences on a miniaturized scale; fertility, immunology, cytology and pharmaceutical screening
US8043849May 4, 2007Oct 25, 2011Thermal GradientThermal cycling device
US8067159Aug 13, 2007Nov 29, 2011Applied Biosystems, LlcMicrofluidics; electromagnetics; electrophoresis; DNA sequence analysis
US8211279Jun 2, 2006Jul 3, 2012Board Of Regents Of The University Of Texas SystemElectrochemistry and electrogenerated chemiluminescence with a single faradaic electrode
US8222023Sep 10, 2008Jul 17, 2012Micronics, Inc.Integrated nucleic acid assays
US8252581Jan 22, 2008Aug 28, 2012Wafergen, Inc.Apparatus for high throughput chemical reactions
US8257925May 16, 2011Sep 4, 2012Applied Biosystems, LlcMethod for detecting the presence of a single target nucleic acid in a sample
US8278071Aug 13, 2007Oct 2, 2012Applied Biosystems, LlcMethod for detecting the presence of a single target nucleic acid in a sample
US8389288Jan 18, 2010Mar 5, 2013Applied Biosystems, LlcDevice for the carrying out of chemical or biological reactions
US8551698Aug 13, 2007Oct 8, 2013Applied Biosystems, LlcMethod of loading sample into a microfluidic device
US8563275Aug 11, 2012Oct 22, 2013Applied Biosystems, LlcMethod and device for detecting the presence of a single target nucleic acid in a sample
US8676383Sep 5, 2007Mar 18, 2014Applied Biosystems, LlcDevice for carrying out chemical or biological reactions
US8702958May 31, 2012Apr 22, 2014Board Of Regents Of The University Of Texas SystemElectrochemistry and electrogenerated chemiluminescence with a single faradaic electrode
US8721161Sep 15, 2005May 13, 2014Alcatel LucentFluid oscillations on structured surfaces
US8721972May 14, 2012May 13, 2014Applied Biosystems, LlcDevice for the carrying out of chemical or biological reactions
US8734003Dec 27, 2005May 27, 2014Alcatel LucentMicro-chemical mixing
US8772017Jun 8, 2012Jul 8, 2014Micronics, Inc.Integrated nucleic acid assays
DE10149684B4 *Oct 9, 2001Feb 17, 2005Clondiag Chip Technologies GmbhVorrichtung zur Halterung eines Substanzbibliothekenträgers
EP1123739A1 *Feb 11, 2000Aug 16, 2001STMicroelectronics S.r.l.Integrated device for microfluid thermoregulation, and manufacturing process thereof
EP1193214A1 *Sep 27, 2000Apr 3, 2002SGS-THOMSON MICROELECTRONICS S.r.l.Integrated chemical microreactor, thermally insulated from detection electrodes, and manufacturing method therefor
EP1269171A1 *Mar 7, 2001Jan 2, 2003Northeastern UniversityParallel array of independent thermostats for column separations
WO2001024930A1 *Sep 29, 2000Apr 12, 2001Mwg Biotech AgDevice for carrying out chemical or biological reactions
WO2001089692A2 *May 24, 2001Nov 29, 2001Micronics IncNucleic acid amplification and detection using microfluidic diffusion based structures
WO2004052527A1 *Dec 10, 2003Jun 24, 2004Knoell Hans Forschung EvMethod and reactor for the amplification of dna
WO2005001435A2 *Aug 21, 2003Jan 6, 2005Univ CaliforniaSystem for autonomous monitoring of bioagents
WO2005082043A2 *Feb 24, 2005Sep 9, 2005Joel GroverThermal cycling device
Classifications
U.S. Classification435/283.1, 422/109, 422/198, 435/289.1, 422/82.11, 435/293.1, 422/68.1, 422/603
International ClassificationB01L3/00, B01J19/00, B01L7/00
Cooperative ClassificationB01L7/525, B01L2300/0816, B01L2300/087, B01J19/0093, B01L2200/0673, B01L7/52, B01L3/5027, B01L2300/0883, B01J2219/00783, B01L2300/1883, B01J2219/00873
European ClassificationB01L3/5027, B01L7/525, B01L7/52, B01J19/00R
Legal Events
DateCodeEventDescription
Jul 23, 2009FPAYFee payment
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Oct 31, 1996ASAssignment
Owner name: BIOMETRA BIOMEDIZINISCHE ANALYTIK GMBH, GERMANY
Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:BAIER, VOLKER;BODNER, ULRICH;DILLNER, ULRICH;AND OTHERS;REEL/FRAME:008224/0322;SIGNING DATES FROM 19960519 TO 19960524